Arylcyclopropylcarboxylic amides as potassium channel openers

ABSTRACT

The present invention provides novel arylcyclopropylcarboxylic amides and related derivatives having the general Formula I  
                 
 
     wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are as defined in the specification, or a nontoxic pharmaceutically acceptable salt, solvate or hydrate thereof which are openers or activators of KCNQ potassium channels. The present invention also provides pharmaceutical compositions comprising said arylcyclopropylcarboxylic amides and to the method of treatment of disorders sensitive to KCNQ potassium channel opening activity such as migraine or a migraine attack, bipolar disorders, epilepsy, acute and chronic pain and anxiety.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This is a non-provisional application which claims the benefit ofU.S. Provisional Application No. 60/428,337 filed Nov. 22, 2002.

FIELD OF THE INVENTION

[0002] The present invention is directed to novelarylcyclopropylcarboxylic amide derivatives which are modulators of KCNQpotassium channels and are therefore useful in treating disordersresponsive to the modulation of the potassium channels. The presentinvention also provides a method of treatment with the novelarylcyclopropylcarboxylic amide derivatives and to pharmaceuticalcompositions thereof.

BACKGROUND OF THE INVENTION

[0003] Potassium (K⁺) channels are considered to be the most diverseclass of ion channels and have several critical roles in cell function.This has been demonstrated in neurons where K⁺ channels are responsible,in part, for determining cell excitability by contributing to membranerepolarization following depolarization, resting membrane potential, andregulation of neurotransmitter release. The M-current has long beendescribed, by electrophysiology recording methods and by pharmacology,as a dominant conductance in controlling neuronal excitability.Pharmacological activation or suppression of M-currents by smallmolecules could have profound effects in controlling neuronalexcitability. Recently, Wang et al., Science, 282:1890-1893, (1998)reported that co-assembly of the KCNQ2 and KCNQ3 potassium channelsunderlies the native M-current in neurons.

[0004] Activation or opening of the KCNQ channel(s), particularly theKCNQ2 or KCNQ2/3 channel(s), mutated or wild type, may prove to bebeneficial in increasing hyperpolarization of neurons, thereby resultingin protection from abnormal synchronous firing during a migraine attack.The present invention provides a solution to the problem of abnormalsynchronous firing of neurons related to migraine headache bydemonstrating that modulators, preferably openers, of KCNQ potassiumchannels increases hyperpolarization of neurons which protects againstabnormal synchronous neuron firing involved in migraine attacks.

[0005] Although the symptom pattern varies among migraine sufferers, theseverity of migraine pain justifies a need for vigorous, yet safe andeffective, treatments and therapies for the great majority of cases.Needed in the art are agents that can be used to combat and relievemigraine (and diseases similar to and mechanistically related tomigraine), and even prevent the recurrence of migraine. Also needed areanti-migraine agents which are effective in the treatment of acutemigraine, as well as in the prodrome phase of a migraine attack. Thus, aclear goal in the art is to discover new, safe, nontoxic and effectiveanti-migraine compounds for use as drugs, and in anti-migrainecompositions and treatments.

[0006] Because migraine afflicts a large percentage of the population,there is a need to discover compounds and agents that are useful intherapeutics and treatments, and as components of pharmaceuticalcompositions, for reducing, ameliorating, or alleviating the pain anddiscomfort of migraine headache and other symptoms of migraine. Thepresent invention satisfies such a need by providing compounds thatfunction as openers of the KCNQ family of potassium channel proteins toserve as anti-migraine agents or drugs and to comprise compositions totreat migraine, as described herein.

[0007] A broad range of cinnamide compounds are known and new compoundscontinue to be reported with a broad range of utility. Some of thesecompounds can be found in the disclosures of WO 00/07993 published Feb.17, 2000, EP 810220A1, published Dec. 3, 1997, U.S. Pat. No. 4,927,838issued May 22, 1990 to Guthrie, et al., U.S. Pat. No. 6,046,239 issuedApr. 4, 2000 to Lennox, et al., WO 00.42013, published Jul. 20, 2000, WO01/10381 published Feb. 15, 2001, WO 01/10380 published Feb. 15, 2001,JP45-14291 published May 21, 1970, and JP2-138159 published May 28,1990. The compounds described in these patents are distinct from thoseof the present invention.

SUMMARY OF THE INVENTION

[0008] The present invention provides novel arylcyclopropylcarboxylicamides and related derivatives having the general Formula I

[0009] wherein R, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined below, ora nontoxic pharmaceutically acceptable salt, solvate or hydrate thereofwhich are openers or activators of KCNQ potassium channels. The presentinvention also provides pharmaceutical compositions comprising saidarylcyclopropylcarboxylic amides and to the method of treatment ofdisorders sensitive to KCNQ potassium channel opening activity such asmigraine or a migraine attack, bipolar disorders, epilepsy, acute andchronic pain and anxiety.

DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention provides novel arylcyclopropylcarboxylicamides and related derivatives which are modulators of the KCNQpotassium channels and which have the general Formula I or apharmaceutically acceptable salt thereof

[0011] wherein R is C₁₋₄ alkyl, CF₃ or hydroxymethyl; R¹ and R² are eachindependently hydrogen, C₁₋₄ alkyl, halogen or morpholin-4-yl; R⁴ isselected from the group consisting of optionally substitutedmorpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl, inwhich said substituent is independently selected from the groupconsisting of C₁₋₄alkyl, dimethylamino, hydroxymethyl, chloro andfluoro; R⁵is hydrogen or fluoro; or R⁴ and R⁵ taken together are —CH═CH—CH═CH— or —CH₂CH₂O—; and R³, R⁶ and R⁷ are each independently selectedfrom hydrogen or fluoro, which are openers of the KCNQ potassiumchannels and are useful in the treatment of disorders which areresponsive to the opening of the KCNQ potassium channels.

[0012] The present invention also provides a method for the treatment oralleviation of disorders associated with KCNQ potassium channelpolypeptides and, in particular, human KCNQ potassium channelpolypeptides in a mammal in need thereof which comprises administeringtogether with a conventional adjuvant, carrier or diluent atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof. Preferably, the compounds ofFormula I are useful in the treatment of migraine or a migraine attack,cluster headaches, bipolar disorder, convulsions, mania, acute mania,epilepsy, anxiety, depression, schizophrenia, functional boweldisorders, stroke, traumatic brain injury, multiple sclerosis,neurodegenerative disorders or alleviating pain such as musculoskeletalpain, post operative pain, surgical pain, inflammatory pain, neuropathicpain such as diabetic neuropathy and pain associated with cancer andfibromyalgia.

[0013] The term “pain” as used herein and in the claims means all typesof acute and chronic pain, such as neuropathic pain, post-operativepain, chronic lower back pain, cluster headaches, herpes neuralgia,phantom limb pain, central pain, dental pain, opioid-resistant pain,visceral pain, surgical pain, bone injury pain, pain during labor anddelivery, pain resulting from burns, including sunburn, post partumpain, migraine, angina pain, and genitourinary tract-related painincluding cystitis and the term also is intended to include nociceptivepain or nociception.

[0014] The term “C₁₋₄ alkyl” as used herein and in the claims meansstraight or branched chain alkyl groups such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl. The term “C₁₋₄ alkoxy” asused herein and in the claims means an oxygen substituted with straightor branched chain alkyl groups and includes groups such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tert-butoxy. Theterm “halogen” as used herein and in the claims is intended to includebromine, chlorine, iodine and fluorine.

[0015] As the compounds of the present invention contain a substitutedcyclopropyl group as part of the structure, the compounds of theinvention exist in either of two geometric isomeric forms, namely as cisor trans isomers. Preferred are the trans isomers in which the arylgroup and the amide group, C(O)NH, are trans to each other. As thecompounds of the present invention possess an asymmetric carbon atom,such as the carbon adjacent to the amide nitrogen and to which thephenyl is attached, the present invention includes the racemate as wellas the individual enantiomeric forms of the compounds of Formula I asdescribed herein and in the claims. Preferred embodiments of compoundsof Formula I include the racemate, a single enantiomer, and in certaininstances a single enantiomer wherein the carbon adjacent to the amidenitrogen and to which the phenyl is attached has the (S)stereochemistry. Mixtures of isomers of the compounds of Formula I orchiral precursors thereof can be separated into individual isomersaccording to methods which are known per se, e.g. fractionalcrystallization, adsorption chromatography or other suitable separationprocesses. Resulting racemates can be separated into antipodes in theusual manner after introduction of suitable salt-forming groupings, e.g.by forming a mixture of diastereosiomeric salts with optically activesalt-forming agents, separating the mixture into diastereomeric saltsand converting the separated salts into the free compounds. Theenantiomeric forms may also be separated by fractionation through chiralhigh pressure liquid chromatography columns, according to proceduresdescribed herein.

[0016] Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms including hydrated forms suchas monohydrate, dihydrate, trihydrate, hemihydrate, tetrahydrate and thelike. The products may be true solvates, while in other cases, theproducts may merely retain adventitious solvent or be a mixture ofsolvate plus some adventitious solvent. It should be appreciated bythose skilled in the art that solvated forms are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

[0017] In the method of the present invention, the term “therapeuticallyeffective amount” means the total amount of each active component of themethod that is sufficient to show a meaningful patient benefit, i.e.,amelioration or healing of conditions which respond to modulation of theKCNQ potassium channels. When applied to an individual activeingredient, administered alone, the term refers to that ingredientalone. When applied to a combination, the term refers to combinedamounts of the active ingredients that result in the therapeutic effect,whether administered in combination, serially or simultaneously. Theterm “KCNQ” as used herein and in the claims means the family of KCNQ2,KCNQ3, KCNQ4, and KCNQ5 potassium channel polypeptides as well asheteromultimers of different individual family members which include butare not limited to KCNQ2/3, KCNQ2/5 and KCNQ3/5. The terms “treat,treating, treatment” as used herein and in the claims means preventing,alleviating or ameliorating diseases and/or symptoms associated withdysfunction of cellular membrane polarization and conductance of humanKCNQ2, KCNQ3, KCNQ4, and KCNQ5 potassium channel polypeptides and, inparticular, migraine and/or symptoms that precede a full-blown migraineattack, neuropathic pain, mania and anxiety.

[0018] The general procedures used to synthesize intermediates and thecompounds of Formula I are described in Reaction Schemes 1-4 and areillustrated in the preparations and examples. Reasonable variations ofthe described procedures, which would be evident to one skilled in theart, are intended to be within the scope of the present invention.

[0019] Reaction Scheme 1 depicts the preparation ofcyclopropanecarboxylic acid derivatives useful as intermediates in thesynthesis of compounds of Formula I. Step 1 of Reaction Scheme 1 depictsthe reaction of an appropriate cinnamic acid of Formula II withO,N-dimethyl-hydroxylamine hydrochloride and triethylamine to furnishcompound of Formula III. Compound of Formula III can be converted tocompound of Formula IV by treatment with trimethylsulfoxonium iodide andsodium hydride. Compound of Formula IV can be hydrolyzed under basicconditions such as aqueous sodium hydroxide followed by acidification togive compound of Formula V.

[0020] Reaction Scheme 2 depicts a general method useful for thepreparation of amines of Formula VIII which are useful intermediates forthe preparation of compounds of Formula I. Compound of Formula VI wasconverted to compound of Formula VII by reaction with hydroxylaminehydrochloride in the presence of a base such as triethylamine. Compoundof Formula VII underwent catalytic hydrogenation to give amine withFormula VIII.

[0021] Reaction Scheme 3 depicts an alternative method useful for thepreparation of amines of Formula VIII. Compound of Formula VI underwentreductive alkylation with ammonia and a reducing agent such as sodiumcyanoborohydride to give compound of Formula VIII.

[0022] Reaction Scheme 4 depicts the preparation of compounds of generalFormula I from the acid of general Formula V and amine of Formula VIII.Reaction Scheme 4 depicts the preparation of compounds of generalFormula I from the acid of general Formula V and amine of generalFormula VIII. The coupling of the acid, V, and amine, VIII is carriedout by methodology well known in the art for the conversion of an acidand an amine to form an amide. Useful reactive derivatives of the acidof Formula VIII include, but are not limited to, activated esters,reactive mixed anhydrides, and acid halides (such as the acid chloride,prepared e.g. with thionyl chloride or oxalyl chloride). A preferredmethod is to condense the acid of Formula V with the amine of FormulaIII in the presence of an appropriate condensing agent, for example,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) ordicyclohexylcarbodiimide (DCC), and a basic tertiary amine, such as4-dimethylaminopyridine (DMAP), in an inert solvent such asdichloromethane. The more preferred method is to couple the acid ofFormula V with the amine of Formula VIII in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (EDC) inthe presence of 4-dimethylaminopyridine (DMAP), triethylamine (Et₃N), indichloromethane.

[0023] In one embodiment, the present invention includes compounds ofFormula I or a pharmaceutically acceptable salt thereof

[0024] wherein R is C₁₋₄ alkyl, CF₃ or hydroxymethyl; R¹ and R² are eachindependently hydrogen, C₁₋₄ alkyl, halogen or morpholin-4-yl; R⁴ isselected from the group consisting of optionally substitutedmorpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl, inwhich said substituent is independently selected from the groupconsisting of C₁₋₄alkyl, dimethylamino, hydroxymethyl, chloro andfluoro; R⁵ is hydrogen or fluoro; or R⁴ and R⁵ taken together are—CH═CH— CH═CH— or —CH₂CH₂O—; and R³, R⁶ and R⁷ are each independentlyselected from hydrogen or fluoro.

[0025] In a preferred embodiment, the invention includes compounds ofFormula Ia or a pharmaceutically acceptable salt thereof

[0026] wherein R is methyl; R¹ and R² are each independently hydrogen,C₁₋₄ alkyl, halogen or morpholin-4-yl; R⁴ is selected from the groupconsisting of optionally substituted morpholin-4-yl, pyridinyl,pyrimidinyl, piperazinyl, and pyrazinyl, in which said substituent isindependently selected from the group consisting of C₁₋₄alkyl,dimethylamino, hydroxymethyl, chloro and fluoro; R⁵ is hydrogen orfluoro; or R⁴ and R⁵ taken together are —CH═CH—CH═CH— or —CH₂CH₂O—; andR³, R⁶ and R⁷ are each independently selected from hydrogen or fluoro.

[0027] In a preferred embodiment, the invention includes compounds ofFormula Ib or a pharmaceutically acceptable salt thereof

[0028] wherein R is hydroxymethyl; R¹ and R² are each independentlyhydrogen, C₁₋₄ alkyl, halogen or morpholin-4-yl; R⁴ is selected from thegroup consisting of optionally substituted morpholin-4-yl, pyridinyl,pyrimidinyl, piperazinyl, and pyrazinyl, in which said substituent isindependently selected from the group consisting of C₁₋₄alkyl,dimethylamino, hydroxymethyl, chloro and fluoro; R⁵ is hydrogen orfluoro; or R⁴ and R⁵ taken together are —CH═CH—CH═CH— or —CH₂CH₂O—; andR³, R⁶ and R⁷ are each independently selected from hydrogen or fluoro.

[0029] Preferred compounds for use in the method of the presentinvention include the compounds of Formula I listed below:

[0030] 2-(2-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide;

[0031] 2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide;

[0032] 2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide;

[0033] 2-(2-fluoro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide;

[0034] 2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide;

[0035] 2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide;

[0036] 2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide;

[0037] 2-(2-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide;

[0038] 2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide;

[0039] 2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide;

[0040] 2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide;

[0041] 2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid(1-naphthalen-2-yl-ethyl)-amide;

[0042] 2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid(1-naphthalen-2-yl-ethyl)-amide;

[0043] 2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyll}-amide;

[0044] 2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyl}-amide;

[0045] 2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(3-pyridin-3-yl-phenyl)-ethyl]-amide;

[0046] 2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid[1-(3-pyridin-3-yl-phenyl)-ethyl]-amide;

[0047] (S)-2-phenyl-cyclopropanecarboxylicacid[1-(3-pyridin-3-yl-phenyl)-ethyl]-amide;

[0048] (S)-2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(6-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide;

[0049] (S)-2-phenyl-cyclopropanecarboxylicacid{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide; and

[0050] (S)-2-(2-fluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide;

[0051] or a pharmaceutically acceptable salt thereof.

Biological Activity KCNQ Patch-Clamp Methods and Results

[0052] Potassium (K⁺) channels are structurally and functionally diversefamilies of K⁺-selective channel proteins which are ubiquitous in cells,indicating their central importance in regulating a number of key cellfunctions [Rudy, B., Neuroscience, 25: 729-749 (1988)]. While widelydistributed as a class, K⁺ channels are differentially distributed asindividual members of this class or as families. [Gehlert, D. R., etal., Neuroscience, 52: 191-205 (1993)]. In general, activation of K⁺channels in cells, and particularly in excitable cells such as neuronsand muscle cells, leads to hyperpolarization of the cell membrane, or inthe case of depolarized cells, to repolarization. In addition to actingas an endogenous membrane voltage clamp, K⁺ channels can respond toimportant cellular events such as changes in the intracellularconcentration of ATP or the intracellular concentration of calcium(Ca²⁺). The central role of K⁺ channels in regulating numerous cellfunctions makes them particularly important targets for therapeuticdevelopment. [Cook, N. S., Potassium channels: Structure,classification, function and therapeutic potential. Ellis Horwood,Chinchester (1990)]. One class of K+ channels, the KCNQ familyexemplified by KCNQ2, KCNQ2/3 heteromultimers, and KCNQ5, is regulatedby transmembrane voltage and plays a potentially important role in theregulation of neuronal excitability [Biervert, C., et al., Science, 279:403-406 (1998); Lerche, C. et al., J. Biol. Chem. 275:22395-22400(2000); Wang, H. et al., Science, 282:1890-1893 (1998)].

[0053] An opener of KCNQ channels, such as the KCNQ2 and KCNQ2/3 channelopener retigabine, exerts its cellular effects by increasing the openprobability of these channels [Main J., Mol Pharmacol 58(2):253-62(2000); Wickenden, A. et al., Mol. Pharm. 58:591-600 (2000)]. Thisincrease in the opening of individual KCNQ channels collectively resultsin the hyperpolarization of cell membranes, particularly in depolarizedcells, produced by significant increases in whole-cell KCNQ-mediatedconductance.

[0054] Whole-cell patch-clamp recordings were made from an HEK 293stable cell line expressing mKCNQ2 channels, maintained in culture for1-2 days. Patch pipettes had initial resistances of 2.5-4 MΩ. Currentswere recorded with an EPC-9 amplifier (HEKA, Lambrecht, Germany)controlled with software (Pulse, HEKA) run on a standard lab PC. Seriesresistance compensation was used during current recording, and set at80%. The series resistance (R) and cell capacitance (C) were determinedelectronically by subtracting the capacitive currents at the onset andoffset of a 5 mV voltage step. The cancellation of whole-cell capacitivetransients was virtually complete in all cells. Analog current signalswere low-pass filtered at 2.9 kHz using a four-pole Bessel filter −3 dB)and stored on a local network server computer at a sampling rate of 1.5kHz. All recordings were performed at room temperature (20-22° C.). Thepipette solution contained (mM): KCl, 150; CaCl₂, 2.5; EGTA, 5; MgCl₂,1; HEPES, 10; pH to 7.3 with KOH, and Osmolality of 290-300 mOsm. Theextracellular solution contained (mM): NaCl, 140; KCl, 2.5; CaCl₂, 2.5;MgCl₂, 1; glucose, 10; HEPES, 10; pH to 7.3 with NaOH, and Osmolality of305-310 mOsm

[0055] For analysis of agents effects on mKCNQ2 currents, the rawcurrent records were displayed on the digital oscilloscope of the Pulsesoftware application. Concentration response data were generated bymeasuring the difference in the steady-state amplitude of current in thepresence of compound at the end of a 600 ms voltage-clamp step from aholding potential of −80 mV. The concentration-response data were fittedwith Hill-type equations:

I=I_(max)/(I+EC₅₀/[A]^(nH)),

[0056] where I is the steady-state current at a given concentration ofagonist [A]; and I_(max), EC₅₀ and nH are parameters estimated from thecurve fit. In some cases the concentration-response data were fittedwith equations consisting of the sum of two Hill-type components.Current-voltage (INV) relationships for agonist-evoked currents wereobtained by performing 600 ms voltage steps (−110 mV to +40 mV) in theabsence and presence of agonist. The effect of a representative compoundof Formula I on KCNQ currents is listed in Table 1. TABLE 1 Example No.EC₅₀ (μM) @ −40 mv) I_(max) (%) 13 0.597 1232

Thallium Assay Methods and Results

[0057] A thallium flux assay was used to detect and characterize openersof KCNQ potassium channels. The thallium assay is generally described inInternational application WO 02/31508 published Apr. 18, 2002. Morespecifically, the thallium influx assay to detect compounds that blockor open the voltage-gated K⁺ channel KCNQ2 is described in Example IV ofthe published WO 02/31508 application.

[0058] For data analysis, the amplitude of the average of the negativecontrols was subtracted from all wells. The amplitudes of the testcompounds were then compared to the value of four standard deviations ofthe negative control wells. The lowest concentration of a test compoundsufficient to generate a signal amplitude greater than or equal to fourstandard deviations from the amplitude of the negative controls wasdefined as the minimal active concentration.

[0059] For generating EC₅₀ values, compounds were serially diluted in1:3 volume increments to produce a 10 point concentration series. EC₅₀values were calculated by fitting the resulting amplitudes to asingle-site logistic equation. EC₅₀ was defined as the concentration oftest compound required to yield 50% of the maximal response. Maximalresponse (Maximal opening) was the largest signal amplitude above thenegative control generated by any concentration of a test compound.

[0060] The following Table 2 contains data which show that compounds ofthe present invention are openers of the KCNQ channels. TABLE 2 ExampleNo. EC₅₀ (μM)  9 0.022 11 1.44 13 0.012 14 0.001 15 0.001 32 0.001 342.21

[0061] In another embodiment, this invention includes pharmaceuticalcompositions comprising at least one compound of Formula I incombination with a pharmaceutical adjuvant, carrier or diluent.

[0062] In still another embodiment, this invention relates to a methodof treatment or prevention of disorders responsive to opening of KCNQpotassium channels in a mammal in need thereof, which comprisesadministering to said mammal a therapeutically effective amount of acompound of Formula I. Preferably, the compounds of Formula I are usefulin the treatment of treatment of migraine or a migraine attack, clusterheadaches, bipolar disorder, convulsions, mania, acute mania, epilepsy,anxiety, depression, schizophrenia, functional bowel disorders, stroke,traumatic brain injury, multiple sclerosis, neurodegenerative disordersor alleviating pain such as musculoskeletal pain, post operative pain,surgical pain, inflammatory pain, neuropathic pain such as diabeticneuropathy and pain associated with cancer and fibromyalgia.

[0063] For therapeutic use, the pharmacologically active compounds ofFormula I will normally be administered as a pharmaceutical compositioncomprising as the (or an) essential active ingredient at least one suchcompound in association with a solid or liquid pharmaceuticallyacceptable carrier and, optionally, with pharmaceutically acceptableadjutants and excipients employing standard and conventional techniques.

[0064] The pharmaceutical compositions include suitable dosage forms fororal, parenteral (including subcutaneous, intramuscular, intradermal andintravenous) bronchial or nasal administration. Thus, if a solid carrieris used, the preparation may be tableted, plated in a hard gelatincapsule in powder or pellet form, or in the form of a troche orlonzenge. The solid carrier may contain conventional excipients such asbinding agents, fillers, tableting lubricants, disintegrants, wettingagents and the like. The tablet may, if desired, be film coated byconventional techniques. If a liquid carrier is employed, thepreparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile vehicle for injection, an aqueous or non-aqueous liquidsuspension, or may be a dry product for reconstitution with water orother suitable vehicle before use. Liquid preparations may containconventional additives such as suspending agents, emulsifying agents,wetting agents, non-aqueous vehicle (including edible oils),preservatives, as well as flavoring and/or coloring agents. Forparenteral administration, a vehicle normally will comprise sterilewater, at least in large part, although saline solutions, glucosesolutions and like may be utilized. Injectable suspensions also may beused, in which case conventional suspending agents may be employed.Conventional preservatives, buffering agents and the like also may beadded to the parenteral dosage forms. Particularly useful is theadministration of a compound of Formula I directly in parenteralformulations. The pharmaceutical compositions are prepared byconventional techniques appropriate to the desired preparationcontaining appropriate amounts of the active ingredient, that is, thecompound of Formula I according to the invention. See, for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., 17th edition, 1985.

[0065] The dosage of the compounds of Formula I to achieve a therapeuticeffect will depend not only on such factors as the age, weight and sexof the patient and mode of administration, but also on the degree ofpotassium channel activating activity desired and the potency of theparticular compound being utilized for the particular disorder ofdisease concerned. It is also contemplated that the treatment and dosageof the particular compound may be administered in unit dosage form andthat the unit dosage form would be adjusted accordingly by one skilledin the art to reflect the relative level of activity. The decision as tothe particular dosage to be employed (and the number of times to beadministered per day is within the discretion of the physician, and maybe varied by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect.

[0066] A suitable dose of a compound of Formula I or pharmaceuticalcomposition thereof for a mammal, including man, suffering from, orlikely to suffer from any condition as described herein is an amount ofactive ingredient from about 0.01 μg/kg to 10 mg/kg body weight. Forparenteral administration, the dose may be in the range of 0.1 μg/kg to1 mg/kg body weight for intravenous administration. For oraladministration, the dose may be in the range about 0.1 μg/kg to 5 mg/kgbody weight. The active ingredient will preferably be administered inequal doses from one to four times a day. However, usually a smalldosage is administered, and the dosage is gradually increased until theoptimal dosage for the host under treatment is determined.

[0067] However, it will be understood that the amount of the compoundactually administered will be determined by a physician, in the light ofthe relevant circumstances including the condition to be treated, thechoice of compound of be administered, the chosen route ofadministration, the age, weight, and response of the individual patient,and the severity of the patient's symptoms.

[0068] The following examples are given by way of illustration and arenot to be construed as limiting the invention in any way inasmuch asmany variations of the invention are possible within the spirit of theinvention.

Description of Specific Embodiments

[0069] Unless otherwise stated, solvents and reagents were used directlyas obtained from commercial sources, and reactions were performed undera nitrogen atmosphere. Flash chromatography was conducted on Silica gel60 (0.040-0.063 particle size; EM Science supply). ¹H NMR spectra wererecorded on a Bruker DRX-500f at 500 MHz; a Bruker DPX-300B at 300 MHz;or a Varian Gemini 300 at 300 MHz. The chemical shifts were reported inppm on the δ scale relative to δTMS=0. The following internal referenceswere used for the residual protons in the following solvents: CDCl₃(δ_(H) 7.26), CD₃OD (δ_(H) 3.30) and DMSO-d₆ (δ_(H) 2.50). Standardacronyms were employed to describe the multiplicity patterns: s(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b(broad), app (apparent). The coupling constant (J) is in hertz. LC/MSwas performed on a Shimadzu LC-10AS liquid chromatograph using aSPD-10AV UV-VIS detector with Mass Spectrometry data determined using aMicromass LC Platform in positive electrospray ionization mode (ESI+).Mass Spectrometry (MS) data was obtained using a standard flow injectiontechnique on a Micromass LC Platform in positive electrospray ionizationmode (ESI+) unless otherwise noted. High resolution mass spectrometry(HRMS) data was obtained using a standard flow injection technique on aFinnigan MAT 900 mass spectrometer in electrospray ionization (ESI)mode. The analytical reverse phase HPLC method is as follows unlessotherwise noted: Column YMC ODS-A C18 S7 (3.0×50 mm), Start % B=0, Final% B=100, Gradient Time=2 min, Flow rate 5 ml/minutes. Wavelength=220 nm,Solvent A=10% MeOH—90% H₂O—0.1% TFA, Solvent B=90% MeOH—10% H₂O—0.1%TFA; and R_(t) in min. Preparative reverse phase HPLC was performed on aShimadzu LC-8A automated preparative HPLC system with detector (SPD-10AVUV-VIS) wavelength and solvent systems (A and B) the same as aboveexcept where otherwise noted.

[0070] The following LCMS conditions were employed for the analysis ofthe compounds of Examples 1-36 and are as follows:

[0071] a) YMC Xterra C18 S7 3.0×50 mm; 0-100% gradient over 2 min; 5mL/min flow rate

[0072] b) Primeshere C18-HC 4.6×30 mm; (5 mM NH₄OAc) 0-100% gradientover 2 min; 4 mL/min flow rate

[0073] c) Xterra C8-HC 4.6×30 mm; (0.05% TFA) 0-100% gradient over 2min; 4 mL/min flow rate

10% CH₃CN-90% H₂O-5 mM NH₄OAc   SolventA

90% CH₃CN-10% H₂O-5 mM NH₄Oac   SolventB

Preparation of Intermediates Preparation 1 Preparation of2-(2-chloro-phenyl)-cyclopropanecarboxylic acid

[0074]

[0075] Step A: 3-(2-Chloro-phenyl)-N-methoxy-N-methyl-acrylamide

[0076] A mixture of 2-chlorocinnamic acid (18.3 g), EDAC.HCl (23 g),DMAP (12.2 g), triethylamine (28 mL), and NH₂OMe.HCl (12 g) in CH₂Cl₂(300 mL) was stirred at room temperature for 16 h. The reaction wasquenched with water, and the organic layer was washed with brine, driedover MgSO₄ and filtered. The filtrated was evaporated in vacuo, and thecrude product was purified by silica gel flash chromatography elutingwith 33% hexanes in ethyl acetate gave the title compound (22 g) as asolid.

[0077]¹H NMR (300 MHz, CDCl₃) δ 8.13 (d, J=15.8 Hz, 1 H), 7.66-7.63 (m,1 H), 7.41-7.38 (m, 1 H), 7.28-7.25 (m, 1 H), 7.04 (d, J=15.8 Hz, 1 H),3.75 (s, 3 H), 3.30 (s, 3 H). MS (M+H)⁺ 226.

Step B: 2-(2-Chloro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide

[0078] NaH (8 g, 60% oil dispersion) was added to a suspension oftrimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature and stirredfor 0.5 h. A solution of3-(2-chloro-phenyl)-N-methoxy-N-methyl-acrylamide (22 g) was added tothe above reaction mixture at 0° C., and the resulting reaction wasallowed to warm to room temperature and stirred for 2 h. The reactionwas quenched with water and the aqueous layer was extracted with CH₂Cl₂.The combined organic layers were washed with brine, dried over MgSO₄,and concentrated in vacuo to give a residue. The residue was purified byflash chromatography over silica gel (elution with 50% hexanes in ethylacetate) to give the title compound (17 g) as an oil.

[0079]¹H NMR (300 MHz, CDCl₃) δ 7.37-7.34 (m, 1 H), 7.20-7.15 (m, 1 H),7.08-7.05 (m, 1 H), 3.73 (s, 3 H), 3.25 (s, 3 H). 2.80-2.74 (m, 1 H),2.35-2.29 (m, 1 H), 1.67-1.60 (m, 1 H), 1.37-1.31 (m, 1 H). MS (M+H)⁺240.

Step C: Preparation of 2-(2-chloro-phenyl)-cyclopropanecarboxylic acid

[0080] A mixture of 2-(2-chloro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide (9.6 g), water (20 mL), and NaOH (3.2 g) in MeOH(40 mL) was refluxed for 3 h. The reaction mixture was cooled down toroom temperature and concentrated in vacuo. The residue was acidified by6 N HCl followed by extraction with CH₂Cl₂. The organic layer was washedwith brine, dried over MgSO₄ and concentrated in vacuo to give the titlecompound (7.8 g).

[0081]¹H NMR (300 MHz, CDCl₃) δ 7.39-7.36 (m, 1 H), 7.20-7.18 (m, 1 H),7.00-7.01 (m, 1 H), 2.85-2.80 (m, 1 H), 1.84-1.80 (m, 1 H), 1.73-1.66(m, 1 H), 1.46-1.39 (m, 1 H). MS (M−H)⁺ 195.

Preparation 2 Preparation of 2-(3-chloro-phenyl)-cyclopropanecarboxylicacid

[0082]

Step A: 3-(3-Chloro-phenyl)-N-methoxy-N-methyl-acrylamide

[0083] A mixture of 3-chlorocinnamic acid (18.3 g), EDAC.HCl (23 g),DMAP (12.2 g), triethylamine (28 mL), and NH(Me)OMe.HCl (12 g) in CH₂Cl₂(300 mL) was stirred at room temperature for 16 h. The reaction wasquenched with water, and the organic layer was washed with brine, driedover MgSO₄ and filtered. The filtrated was evaporated in vacuo, and thecrude product was purified by silica gel flash chromatography elutingwith 33% hexanes in ethyl acetate gave the title compound (20 g) as asolid.

Step B: 2-(3-Chloro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide

[0084] NaH (8 g, 60% oil dispersion) was added to a suspension oftrimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature and stirredfor 0.5 h. A solution of3-(3-chloro-phenyl)-N-methoxy-N-methyl-acrylamide (19.5 g) was added tothe above reaction mixture at 0° C., and the resulting reaction wasallowed to warm to room temperature and stirred for 2 h. The reactionwas quenched with water and the aqueous layer was extracted with CH₂Cl₂.The combined organic layers were washed with brine, dried over MgSO₄,and concentrated in vacuo to give a residue. The residue was purified byflash chromatography over silica gel (elution with 50% hexanes in ethylacetate) to give the title compound (14 g) as an oil.

[0085]¹H NMR (300 MHz, CDCl₃) δ 7.20-7.01 (m, 3 H), 3.70 (s, 3 H), 3.23(s, 3 H). 2.48-2.43 (m, 2 H), 1.67-1.60 (m, 1 H), 1.32-1.25 (m, 1 H). MS(M+H)⁺ 240.

Step C: Preparation of 2-(2-chloro-phenyl)-cyclopropanecarboxylic acid

[0086] A mixture of 2-(3-chloro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide (9.6 g), water (20 mL), and NaOH (3.2 g) in MeOH(40 mL) was refluxed for 3 h. The reaction mixture was cooled down toroom temperature and concentrated in vacuo. The residue was acidified by6 N HCl followed by extraction with CH₂Cl₂. The organic layer was washedwith brine, dried over MgSO₄ and concentrated in vacuo to give the titlecompound (7.4 g).

[0087]¹H NMR (300 MHz, CDCl₃) δ 7.28-7.18 (m, 1 H), 7.09 (s, 1 H),7.01-6.99 (m, 1 H), 2.58-2.56 (m, 1 H), 1.91-1.88 (m, 1 H), 1.69-1.65(m, 1 H), 1.41-1.39 (m, 1 H). MS (M−H)⁺ 195.

Preparation 3 Preparation of 2-(4-chloro-phenyl)-cyclopropanecarboxylicacid

[0088]

Step A: 3-(4-Chloro-phenyl)-N-methoxy-N-methyl-acrylamide

[0089] A mixture of 4-chlorocinnamic acid (18.3 g), EDAC.HCl (23 g),DMAP (12.2 g), triethylamine (28 mL), and NH₂OMe.HCl (12 g) in CH₂Cl₂(300 mL) was stirred at room temperature for 16 h. The reaction wasquenched with water, and the organic layer was washed with brine, driedover MgSO₄ and filtered. The filtrated was evaporated in vacuo, and thecrude product was purified by silica gel flash chromatography elutingwith 33% hexanes in ethyl acetate gave the title compound (19.5 g) as asolid.

Step B: 2-(4-Chloro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide

[0090] NaH (8 g, 60% oil dispersion) was added to a suspension oftrimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature and stirredfor 0.5 h. A solution of3-(4-chloro-phenyl)-N-methoxy-N-methyl-acrylamide (19.5 g) was added tothe above reaction mixture at 0° C., and the resulting reaction wasallowed to warm to room temperature and stirred for 2 h. The reactionwas quenched with water and the aqueous layer was extracted with CH₂Cl₂.The combined organic layers were washed with brine, dried over MgSO₄,and concentrated in vacuo to give a residue. The residue was purified byflash chromatography over silica gel (elution with 50% hexanes in ethylacetate) to give the title compound (13 g) as an oil.

[0091]¹H NMR (300 MHz, CDCl₃) δ 7.25 (d, J=6.66, 2 H), 7.06 (d, J=6.66Hz, 2 H), 3.68 (s, 3 H), 3.23 (s, 3 H). 2.48-2.38 (m, 2 H), 1.65-1.60(m, 1 H), 1.29-1.23 (m, 1 H). MS (M+H)⁺ 240.

Step C: Preparation of 2-(4-chloro-phenyl)-cyclopropanecarboxylic acid

[0092] A mixture of 2-(4-chloro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide (9.6 g), water (20 mL), and NaOH (3.2 g) in MeOH(40 mL) was refluxed for 3 h. The reaction mixture was cooled down toroom temperature and concentrated in vacuo. The residue was acidified by6 N HCl followed by extraction with CH₂Cl₂. The organic layer was washedwith brine, dried over MgSO₄ and concentrated in vacuo to give the titlecompound (7.3 g).

[0093]¹H NMR (300 MHz, CDCl₃) δ 7.27 (d, J=10 Hz, 2 H), 7.05 (d, J=10Hz, 2 H), 2.58-2.56 (m, 1 H), 1.87-1.85 (m, 1 H), 1.68-1.65 (m, 1 H),1.39-1.36 (m, 1 H), MS (M−H)⁺ 195.

Preparation 4 Preparation of 2-(2-fluoro-phenyl)-cyclopropanecarboxylicacid

[0094]

Step A: 3-(2-Fluoro-phenyl)-N-methoxy-N-methyl-acrylamide

[0095] A mixture of 2-fluorocinnamic acid (16.6 g), EDAC.HCl (23 g),DMAP (12.2 g), triethylamine (28 mL), and NH₂OMe.HCl (12 g) in CH₂Cl₂(300 mL) was stirred at room temperature for 16 h. The reaction wasquenched with water, and the organic layer was washed with brine, driedover MgSO₄ and filtered. The filtrated was evaporated in vacuo, and thecrude product was purified by silica gel flash chromatography elutingwith 33% hexanes in ethyl acetate gave the title compound (20 g) as asolid.

[0096]¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J=16.0 Hz, 1 H), 7.56-7.53 (m,1 H), 7.34-7.31 (m, 1 H), 7.17-7.05 (m, 2 H), 3.76 (s, 3 H), 3.31 (s, 3H). MS (M+H)⁺ 210.

Step B: 2-(2-Fluoro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide

[0097] NaH (8 g, 60% oil dispersion) was added to a suspension oftrimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature and stirredfor 0.5 h. A solution of3-(2-fluoro-phenyl)-N-methoxy-N-methyl-acrylamide (19.5 g) was added tothe above reaction mixture at 0° C., and the resulting reaction wasallowed to warm to room temperature and stirred for 2 h. The reactionwas quenched with water and the aqueous layer was extracted with CH₂Cl₂.The combined organic layers were washed with brine, dried over MgSO₄,and concentrated in vacuo to give a residue. The residue was purified byflash chromatography over silica gel (elution with 50% hexanes in ethylacetate) to give the title compound (16 g) as an oil.

[0098]¹H NMR (300 MHz, CDCl₃) δ 7.13-7.08 (m, 1 H), 7.01-6.92 (m, 2 H),3.66 (s, 3 H), 3.19 (s, 3 H). 2.58-2.54 (m, 1 H), 2.40-2.35 (m, 1 H),1.60-1.54 (m, 1 H), 1.32-1.25 (m, 1 H). MS (M+H)⁺ 224.

Step C: Preparation of 2-(2-fluoro-phenyl)-cyclopropanecarboxylic acid

[0099] A mixture of 2-(2-fluoro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide (8.92 g), water (20 mL), and NaOH (3.2 g) in MeOH(40 mL) was refluxed for 3 h. The reaction mixture was cooled down toroom temperature and concentrated in vacuo. The residue was acidified by6 N HCl followed by extraction with CH₂Cl₂. The organic layer was washedwith brine, dried over MgSO₄ and concentrated in vacuo to give the titlecompound (7 g).

[0100]¹H NMR (300 MHz, CDCl₃) δ 7.26-7.18 (m, 1 H), 7.08-6.95 (m, 2 H),2.75-2.71 (m, 1 H), 1.95-1.91 (m, 1 H), 1.70-1.63 (m, 1 H), 1.49-1.43(m, 1 H).

Preparation 5 Preparation of 2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid

[0101]

Step A: 3-(3-Fluoro-phenyl)-N-methoxy-N-methyl-acrylamide

[0102] A mixture of 3-fluorocinnamic acid (16.6 g), EDAC.HCl (23 g),DMAP (12.2 g), triethylamine (28 mL), and NH₂OMe.HCl (12 g) in CH₂Cl₂(300 mL) was stirred at room temperature for 16 h. The reaction wasquenched with water, and the organic layer was washed with brine, driedover MgSO₄ and filtered. The filtrated was evaporated in vacuo, and thecrude product was purified by silica gel flash chromatography elutingwith 33% hexanes in ethyl acetate gave the title compound (20.2 g) as asolid.

[0103]¹H NMR (300 MHz, CDCl₃) δ 7.70 (d, J=15.81 Hz, 1 H), 7.36-7.23 (m,3 H), 7.08-6.99 (m, 2 H), 3.77 (s, 3 H), 3.31 (s, 3 H). MS (M+H)⁺ 210.

Step B: 2-(3-Fluoro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide

[0104] NaH (8 g, 60% oil dispersion) was added to a suspension oftrimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature and stirredfor 0.5 h. A solution of3-(3-fluoro-phenyl)-N-methoxy-N-methyl-acrylamide (20 g) was added tothe above reaction mixture at 0° C., and the resulting reaction wasallowed to warm to room temperature and stirred for 2 h. The reactionwas quenched with water and the aqueous layer was extracted with CH₂Cl₂.The combined organic layers were washed with brine, dried over MgSO₄,and concentrated in vacuo to give a residue. The residue was purified byflash chromatography over silica gel (elution with 50% hexanes in ethylacetate) to give the title compound (18 g) as an oil.

[0105]¹H NMR (300 MHz, CDCl₃) δ 7.25-7.18 (m, 1 H), 6.93-6.78 (m, 2 H),3.69 (s, 3 H), 3.23 (s, 3 H). 2.53-2.44 (m, 2 H), 1.67-1.60 (m, 1 H),1.30-1.25 (m, 1 H). MS (M+H)⁺ 224.

Step C: Preparation of 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid

[0106] A mixture of 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide (8.96 g), water (20 mL), and NaOH (3.2 g) in MeOH(40 mL) was refluxed for 3 h. The reaction mixture was cooled down toroom temperature and concentrated in vacuo. The residue was acidified by6 N HCl followed by extraction with CH₂Cl₂. The organic layer was washedwith brine, dried over MgSO₄ and concentrated in vacuo to give the titlecompound (7.1 g).

[0107]¹H NMR (300 MHz, CDCl₃) δ 7.28-7.21 (m, 1 H), 7.94-6.88 (m, 2 H),6.81-6.76 (m, 1 H), 2.60-2.57 (m, 1 H), 1.92-1.87 (m, 1 H), 1.71-1.66(m, 1 H), 1.42-1.37 (m, 1 H). MS (M−H)⁺ 179.

Preparation 6 Preparation of 2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid

[0108]

Step A: 3-(4-Fluoro-phenyl)-N-methoxy-N-methyl-acrylamide

[0109] A mixture of 4-fluorocinnamic acid (16.6 g), EDAC.HCl (23 g),DMAP (12.2 g), triethylamine (28 mL), and NH₂OMe.HCl (12 g) in CH₂Cl₂(300 mL) was stirred at room temperature for 16 h. The reaction wasquenched with water, and the organic layer was washed with brine, driedover MgSO₄ and filtered. The filtrated was evaporated in vacuo, and thecrude product was purified by silica gel flash chromatography elutingwith 33% hexanes in ethyl acetate gave the title compound (20.5 g) as asolid.

[0110]¹H NMR (300 MHz, CDCl₃) δ 7.71 (d, J=15.71 Hz, 1 H), 7.56-7.53 (m,2 H), 7.08-7.03 (m, 1 H), 6.92 (d, J=15.71 Hz, 1 H), 3.75 (s, 3 H), 3.30(s, 3 H). MS (M+H)⁺ 210.

Step B: 2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide

[0111] NaH (8 g, 60% oil dispersion) was added to a suspension oftrimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature and stirredfor 0.5 h. A solution of3-(4-fluoro-phenyl)-N-methoxy-N-methyl-acrylamide (20.4 g) was added tothe above reaction mixture at 0° C., and the resulting reaction wasallowed to warm to room temperature and stirred for 2 h. The reactionwas quenched with water and the aqueous layer was extracted with CH₂Cl₂.The combined organic layers were washed with brine, dried over MgSO₄,and concentrated in vacuo to give a residue. The residue was purified byflash chromatography over silica gel (elution with 50% hexanes in ethylacetate) to give the title compound (15 g) as an oil.

[0112]¹H NMR (300 MHz, CDCl₃) δ 7.11-6.93 (m, 4 H), 3.69 (s, 3 H), 3.23(s, 3 H). 2.53-2.44 (m, 2 H), 1.64-1.57 (m, 1 H), 1.27-1.25 (m, 1 H). MS(M+H)⁺ 224.

Step C: Preparation of 2-(4-fluoro-phenyl)-cyclopropanecarboxylic acid

[0113] A mixture of 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide (8.96 g), water (20 mL), and NaOH (3.2 g) in MeOH(40 mL) was refluxed for 3 h. The reaction mixture was cooled down toroom temperature and concentrated in vacuo. The residue was acidified by6 N HCl followed by extraction with CH₂Cl₂. The organic layer was washedwith brine, dried over MgSO₄ and concentrated in vacuo to give the titlecompound (7.1 g).

[0114]¹H NMR (300 MHz, CDCl₃) δ 7.10-6.94 (m, 4 H), 2.60-2.57 (m, 1 H),1.87-1.82 (m, 1 H), 1.69-1.64 (m, 1 H), 1.40-1.35 (m, 1 H).

Preparation 7 Preparation of2-(2,5-difluoro-phenyl)-cyclopropanecarboxylic acid

[0115]

Step A: 3-(2,5Difluoro-phenyl)-N-methoxy-N-methyl-acrylamide

[0116] A mixture of 2,5-difluorocinnamic acid (18.4 g), EDAC.HCl (23 g),DMAP (12.2 g), triethylamine (28 mL), and NH₂OMe.HCl (12 g) in CH₂Cl₂(300 mL) was stirred at room temperature for 16 h. The reaction wasquenched with water, and the organic layer was washed with brine, driedover MgSO₄ and filtered. The filtrated was evaporated in vacuo, and thecrude product was purified by silica gel flash chromatography elutingwith 33% hexanes in ethyl acetate gave the title compound (22.1 g) as asolid.

[0117]¹H NMR (300 MHz, CDCl₃) δ 7.79 (d, J=15.96 Hz, 1 H), 7.27-7.22 (m,1 H), 7.05-6.99 (m, 3 H), 3.79 (s, 3 H), 3.30 (s, 3 H). MS (M+H)⁺ 228.

Step B: 2-(2,5difluoro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide

[0118] NaH (8 g, 60% oil dispersion) was added to a suspension oftrimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature and stirredfor 0.5 h. A solution of3-(2,5-difluoro-phenyl)-N-methoxy-N-methyl-acrylamide (21 g) was addedto the above reaction mixture at 0° C., and the resulting reaction wasallowed to warm to room temperature and stirred for 2 h. The reactionwas quenched with water and the aqueous layer was extracted with CH₂Cl₂.The combined organic layers were washed with brine, dried over MgSO₄,and concentrated in vacuo to give a residue. The residue was purified byflash chromatography over silica gel (elution with 50% hexanes in ethylacetate) to give the title compound (18 g) as an oil.

[0119]¹H NMR (300 MHz, CDCl₃) δ 6.96-6.93 (m, 1 H), 6.86-6.82 (m, 1 H),6.72-6.67 (m, 1 H), 3.71 (s, 3 H), 3.24 (s, 3 H). 2.69-2.60 (m, 1 H),2.38-2.42 (m, 1 H), 1.670-1.60 (m, 1 H), 1.1.31-1.26 (m, 1 H). MS (M+H)⁺242.

Step C: Preparation of 2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid

[0120] A mixture of 2-(2,5-difluoro-phenyl)-cyclopropanecarboxylic acidmethoxy-methyl-amide (9.6 g), water (20 mL), and NaOH (3.2 g) in MeOH(40 mL) was refluxed for 3 h. The reaction mixture was cooled down toroom temperature and concentrated in vacuo. The residue was acidified by6 N HCl followed by extraction with CH₂Cl₂. The organic layer was washedwith brine, dried over MgSO₄ and concentrated in vacuo to give the titlecompound (7.8 g).

[0121]¹H NMR (300 MHz, CDCl₃) δ 7.02-6.86 (m, 2 H), 6.68-6.62 (m, 1 H),2.74-2.68 (m, 1 H), 1.94-1.89 (m, 1 H), 1.71-1.67 (m, 1 H), 1.44-1.39(m, 1 H).

Preparation 8 Preparation of{1-[3-(1-Amino-ethyl)-phenyl]-pyrrolidin-3-yl}-dimethyl-amine

[0122]

Step A: [(S)-1-(3-Bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester

[0123] To a solution of (S)-1-(3-bromo-phenyl)-ethylamine (8 g, 40 mmol)and Et₃N (8.4 mL, 60 mmol) in CH₂Cl₂ (200 mL) was added di-tert-butyldicarbonate (8.7 g, 40 mmol), and the reaction mixture was stirred atroom temperature for 4 h. HCl 0.25 N (100 mL) was added and the twolayers were separated. The organic layer was dried over anhydrousmagnesium sulfate and filtered, and the filtrate was concentrated invacuo to provide the title compound (12 g) as a white solid.

[0124]¹H NMR (CDCl₃, 400 MHz): δ 1.42 (m, 12 H), 4.76 (m, 3 H), 7.1-7.3(m, 2 H), 7.36 (d, J=7.1 Hz, 1H). 7.46 (s, 1 H)

Step B: {1-[3-(3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyl}-carbamicacid tert-butyl ester

[0125] A mixture of (S )[1-(3-bromo-phenyl)-ethyl]-carbamic acidtert-butyl ester (6 g), (3R)-3-(dimethylamino)-pyrrolidine (4.56 g),Pd₂(dba)₃ (1.83 g), di-t-butyl-biphenylphosphine (600 mg), K₃PO₄ (8.48g) in DME (40 mL) was stirred at reflux for 16 h. The reaction mixturewas cooled down to room temperature, diluted with methylene chloride,and filtered. The filtrated was evaporated in vacuo, and the crudeproduct was purified by Flash Chromatography using Biotage eluting with20% MeOH in ethyl acetate to give the title compound (1.8 g) as an oil.MS (M+H)⁺ 334.

Step C: 1-[3-(1-Amino-ethyl)-phenyl]-pyrrolidin-3-yl}-dimethyl-amine

[0126] A mixture of{1-[3-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyl}-carbamic acidtert-butyl ester (1.8 g) and 4 ml of 4 N HCl in ethyl acetate (10 mL) at50° C. was stirred for 2 h. After concentration, the residue wasneutralized with 10 N NaOH and extracted with methylene chloride. Theorganic layer was washed with brine, dried over Na₂SO₄, and concentratedto give the crude product (1.25 g) as an oil. MS (M+H)⁺ 234.

Preparation 9 Preparation of(R)-2-Amino-2-(4-fluoro-3-morpholin-4-yl-phenyl)-ethanol

[0127]

Step A: 2-Bromo-1-fluoro-4-vinyl-benzene

[0128] To a suspension of Ph₃PCH₃Br (57 g) in THF (240 mL) at 0° C. wasdropwise added n-BuLi (1.6 N, 100 mL). The resulting mixture was allowedto warm to room temperature and stirred for 1 h. After recooling to 0°C., a solution of 3-bromo-4-fluoro-benzaldehyde (20.3 g) in THF (20 mL)was added. The resulting mixture was allowed to warm to room temperatureand stirred for 1 h. The reaction mixture was quenched with water,concentrated, and extracted with methylene chloride. The combinedorganic layers were dried over magnesium sulfate, concentrated undervacuum. The crude product was purified by flash chromatography elutingwith 10% ethyl acetate in hexanes to give the title compound as an oil(18 g).

[0129]¹H NMR (CDCl₃): δ 7.59-7.56 (m, 1 H), 7.31-7.27 (m, 1 H), 7.05 (t,J=8.4 Hz, 1 H), 6.65 (dd, J=17.7, 11.1 Hz, 1 H), 6.55 (d, J=17.4 Hz, 1H), 5.28 (d, J=10.8 Hz, 1 H).

Step B: 4-(2-Fluoro-5-vinyl-phenyl)-morpholine

[0130] A mixture of 2-bromo-1-fluoro-4-vinyl-benzene (8 g), morpholine(20 mL), Pd₂(dba)₂ (1.83 g), di-t-butyl-biphenylphosphine (1.2 g), K₃PO₄(17 g) in DME (60 mL) was stirred at reflux for 4 h. The reactionmixture was cooled down to room temperature, diluted with methylenechloride, and filtered. The filtrate was concentrated in vacuo. Thecrude product was purified by Flash Chromatography of Biotage elutingwith 7% ethyl acetate in hexanes to give the title compound as an oil (5g).

[0131]¹H NMR (CDCl₃): δ 7.24-6.93 (m, 3 H), 6.68 (dd, J=17.7, 10.8 Hz, 1H), 5.66 (d, J=17.4 Hz, 1 H), 5.22 (d, J=10.8 Hz, 1 H). 3.88 (m, 4H),3.10 (m, 4H). MS (M+H)⁺ 208.

Step C: (R )-4-of[1-(Fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-carbamic acidtert-butyl ester

[0132] Sodium hydroxide (3.6 g) was dissolved in water (220 mL). 10 mLof this solution was used to dissolve potassium osmium (VI) oxidedihydrate (434 mg) to get a purple suspension. The rest of the sodiumhydroxide solution was treated with t-butyl carbamate (10.666 g) inn-propanol (120 mL), followed by addition of t-butyl hypochlorite (11mL). This solution was stirred for 5 min, then (DHQD)₂PHAL (1466 mg) inn-propanol (120 mL) was added, followed by a solution of4-(2-Fluoro-5-vinyl-phenyl)-morpholine (5 g) in n-propanol (206 mL) anda solution of potassium osmium (VI) oxide dihydrate previously made. Thereaction mixture was stirred at room temperature for 0.5 h. The reactionmixture was quenched with saturated Na₂SO₃ solution. Afterconcentration, the residue was extracted with ethyl acetate. Thecombined organic layers were dried over magnesium sulfate, concentratedunder vacuum. The crude product was purified by flash chromatographyeluting with 33% ethyl acetate in hexanes to give the title compound asa solid (2.2 g).

[0133]¹H NMR (CDCl₃): δ 7.03-6.83 (m,3 H), 5.19 (br s, 1 HO, 4.68 (br s,1 H), 3.87 (m, 6 H), 3.09 (m, 4 H), 1.44 (s, 9 H). MS (M+H)⁺ 341.

Step D: (R)-2-Amino-2-(4-fluoro-3-morpholin-4-yl-phenyl)-ethanol

[0134] A solution of TFA (5 mL) and (R)-[1-(fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-carbamic acidtert-butyl ester(1.2 g) in methylene chloride (15 mL) was stirred for 2h. After concentration, the residue was neutralized with 10 N NaOH andextracted with methylene chloride. The organic layer was washed withbrine, dried over Na₂SO₄, and concentrated in vacuo to give the titlecompound as a solid (720 mg).

[0135]¹H NMR (CDCl₃): δ 7.07-6.87 (m, 3 H), 4.04-4.00 (m, 1 H),3.87-3.84 (m, 4 H), 3.73-3.68 (m, 1 H), 3.55-3.52 (m, 1 H), 3.09-3.06(m, 4 H). MS (M+H)⁺ 241.

Preparation 10 Preparation of (R)-2-Amino-2-naphthalen-2-yl-ethanolhydrochloride

[0136]

Step A: (R)-(2-Hydroxy-1-naphthalen-2-yl-ethyl)-carbamic acid tert-butylester

[0137] Sodium hydroxide (1.89 g, 16 mmol) was dissolved in water (115mL). 5.4 mL of this solution was used to dissolve potassium osmium (VI)oxide dihydrate (240 mg) to get a purple suspension. The rest of thesodium hydroxide solution was treated with t-butyl carbamate (5.580 g,47.1 mmol) in n-propanol (54 mL), followed by addition of t-butylhypochlorite (5.4 mL, 47.1 mmol). This solution was stirred for 5 min,then (DHQD)₂PHAL (630 mg) in n-propanol (54 mL) was added, followed by asolution of 2-vinylnaphthalene (2.5 g, 16 mmol) in n-propanol (54 mL)and a solution of potassium osmium (VI) oxide dihydrate previously made.The reaction mixture was stirred at room temperature for 0.5 hr. Thereaction mixture was quenched with saturated NaHSO₃ solution. Afterconcentration, the residue was extracted with ethyl acetate. Thecombined organic layer was dried over magnesium sulfate, concentratedunder vacuum. The crude product was purified by flash chromatographywith 20% ethyl acetate in hekanes to give the title compound (2.6 g) asa solid.

[0138]¹H NMR (CDCl₃): δ 7.83-7.74 (m, 4 H), 7.47-7.37 (m, 3 H), 5.39 (brs, 1 H), 4.91 (br s, 1 H), 3.90 (d, J=3.9 Hz, 2 H), 1.44 (s, 9 H). MS(M+H)⁺ 288.

Step B: (R)-2-Amino-2-naphthalen-2-yl-ethanol hydrochloride

[0139] (R)-(2-Hydroxy-1-naphthalen-2-yl-ethyl)-carbamic acid tert-butylester (2.5 g) and 9 mL of 4 N HCl in ethyl acetate at 50° C. was stirredfor 2 h. After concentration, the residue was neutralized with 10 N NaOHand extracted with methylene chloride. The organic layer was washed withbrine, dried over Na₂SO₄, and concentrated to give the title compound(1.2 g) as a solid which was used in the next step without furtherpurification. MS (M+H)⁺ 188.

Preparation 11 Preparation of (S)-1-(3-pyridin-3-yl-phenyl)-ethylamine

[0140]

[0141] To a solution of (S)-1-(3-bromo-phenyl)-ethyl]-carbamic acidtert-butyl ester (1.5 g, 5 mmol) and pyridine-3-boronic acid (921 mg,7.5 mmol) in ethyleneglycoldimethylether (25 mL) in a sealed tube wereadded cesium carbonate (3.25 g, 10 mmol) and water (10 mL). Argon wasbubbled into the above mixture for 10 min, and Pd(PPh₃)₄ (289 mg, 0.25mmol) was added. The reaction mixture was stirred at 100° C. for 18 hand cooled down to room temperature. Ethyl acetate (100 mL) was added,the resulting solution was washed with NH₄Cl (sat.) (2×100 mL), theorganic layer was dried over anhydrous magnesium sulfate, filtered andthe filtrate was concentrated in vacuo. The crude product was diluted inCH₂Cl₂ (30 mL) and trifluoroacetic acid (10 mL). The reaction mixturewas agitated for 1 h and concentrated in vacuo. The residue was purifiedby solid phase extraction (SCX cartridge, silca gel benzene sulfonicacid linked) to give the title product (424 mg) as a yellow oil.

[0142]¹H NMR (CDCl₃, 400 MHz): δ 1.26 (d, 3 H, J=6.6 Hz), 3.90 (q, 1 H,J=6.6 Hz), 6.87 ( dd, 1H, J=4.8, 7.8 Hz), 7.2-7.35 (m, 3H), 7.45-7.55(m, 2H), 8.64 (s, 1H),9.11 (s, 1H).

Preparation 12 Preparation of(S)-1-f3-(6-Chloro-pyridin-3-yl)-phenyl]-ethylamine

[0143]

Step A: [(S)-1-(phenyl 3-Boronic acid)-ethyl]-carbamic acid tert-butylester

[0144] (S)-1-(3-Bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (5g, 16.6 mmol) were added in THF (100 mL)and cooled to −78° C.,methyllithium (11.8 mL, 1.4M in Et₂O, 16.6 mmol) was added, and thereaction mixture was stirred for 5 min. tert-Butyllithium (19.6 mL, 1.7M in pentane, 33.4 mmol) was added, the reaction mixture was stirred for5 min, and trimethylborate (2.82 mL, 24.9 mmol) was added rapidly. Thereaction mixture was agitated for 1 h, NH₄Cl (sat.) (100 mL) was added,and the resulting solution was allowed to reach 23° C. The reactionmixture was extracted with ethyl acetate (3×100 mL), the organic layerwas dried over anhydrous magnesium sulfate and filtered, and thefiltrate was concentrated in vacuo. The crude product was purified byflash chromatography (30% EtOAC/Hex.) to provide the title compound (2.7g) as white solid.

[0145]¹H NMR (DMSO d₆, 400 MHz): δ 1.2-1.4 (m, 12 H), 4.6-4.7 (m, 3 H),7.2-7.4 (m, 2 H), 7.6-7.8 (m, 2 H).

Step B: (S)-1-[3-(6-chloro-pyridin-3-yl)-phenyl]-ethylamine

[0146] To a solution of (S)-1-(phenyl-3-boronic acid)-ethyl]-carbamicacid tert-butyl ester (1.29 g, 4.86 mmol) and 2-chloro-5-Iodo-pyridine(1.4 g, 11.4 mmol) in ethyleneglycoldimethylether (25 mL) in a sealedtube were added cesium carbonate (4.75 g, 14.6 mmol) and water (5 mL).Argon was bubbled in to the above mixture for 10 min, and Pd(PPh₃)₄ (280mg, 0.24 mmol) was added. The reaction mixture was stirred at 100° C.for 18 hand then cooled down to room temperature. Ethyl acetate (100 mL)was added, the resulting solution was washed with NH₄Cl (sat.) (2×100mL), and the organic layer was dried over anhydrous magnesium sulfateand filtered. The filtrate was concentrated in vacuo and the crudeproduct was diluted in CH₂Cl₂ (30 mL) and trifluoroacetic acid (10 mL).The reaction mixture was agitated for 1 h and concentrated in vacuo. Theresidue was purified by solid phase extraction (SCX cartridge, silca gelbenzene sulfonic acid linked) to give the title product (785 mg, 69%) asyellow oil.

[0147]¹H NMR (DMSO d₆, 400 MHz): δ 1.28 (d, 3 H, J=6.8 Hz), 4.04 (q, 1H, J=6.8 Hz), 7.4-7.45 (m, 2H), 7.5-7.55 (m, 1H), 7.61 (d, 1H J =7.8Hz,), 7.72 (s, 1H), 8.15 (dd, 1H, J=8.3, 2.5 Hz,), 8.73 (d, 1H, J=3.3Hz).

Preparation 13 Preparation of(S)-1-[3-(6-fluoro-pyridin-3-yl)-phenyl]-ethylamine

[0148]

[0149] To a solution of (s)-1-(3-Bromo-phenyl)-ethyl]-carbamic acidtert-butyl ester (2.3 g, 7.6 mmol) and 2-fluoropyridine-3-boronic acid(1 g, 7.09 mmol in ethyleneglycoldimethylether (30 mL) were added cesiumcarbonate (6.3 g, 19.3 mmol) and water (5 mL. Argon was bubbled into theabove solution for 10 min, and Pd(PPh₃)₄ (372 mg, 0.32 mmol) was added.The reaction mixture was stirred at 100° C. for 18 h and then cooleddown to room temperature. Ethyl acetate (100 mL) was added, theresulting solution was washed with NH₄Cl (sat.) (2×100 mL), and theorganic layer was dried over anhydrous magnesium sulfate and filtered.The filtrate was concentrated in vacuo and the crude product was dilutedin CH₂Cl₂ (30 mL) and trifluoroacetic acid (10 mL). The reaction mixturewas agitated for 1 h and concentrated in vacuo. The residue was purifiedby solid phase extraction (SCX cartridge, silca gel benzene sulfonicacid linked) to give the title product (1.18 g) as brown oil.

[0150]¹H NMR (DMSO d₆, 400 MHz): δ 1.26 (d, 3 H, J=6.6 Hz), 4.06 (q, 1H, J=6.6 Hz), 7.28 (dd, 1H J=8.6, 3.3 Hz,), 7.4-7.45 (m, 2H), 7.5-7.55(m, 1H), 7.71 (s, 1H), 8.27 (dd, 1H J=8.6, 2.8 Hz,), 8.54 (d, 1H J=2.5Hz,).

EXAMPLES Example 1 2-(4-chloro-phenyl)-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide

[0151]

[0152] A mixture of 1-(2,3-dihydro-benzofuran-5-yl)-ethylamine (0.1mmol), 2-(4-Chloro-phenyl)-cyclopropanecarboxylic acid (0.1 mmol),EDAC.HCl (0.2 mmol), DMAP (0.2 mmol), and triethylamine (0.4 mmol) indichloromethane (2 mL) was stirred at room temperature overnight. Thereaction mixture was purified by flash chromatography eluting with 50%hexanes in ethyl acetate to give the title compound (23 mg) as a solid.

[0153]¹H NMR (CDCl₃): δ 7.24-7.16 (m, 3 H), 7.07-6.96 (m, 3 H),6.75-6.71 (m, 1 H), 5.09-5.04 (m, 1 H), 4.59-4.53 (m, 2 H), 3.22-3.15(m, 2 H), 2.47-2.43 (m, 1 H), 1.63-1.46 (m, 5 H), 1.19-1.15 (m, 1 H). MS(M+H)⁺ 342. HPLC rt: 1.46 min (method a)

Examples 2-7

[0154] Examples 2-7 were prepared from appropriate acids by the generalprocedure used to prepare Example 1. HPLC Mass Example rt (min), (M +H)⁺ No. Structure Chemical Name method m/z 2

2-(2-Chloro-phenyl)- cyclopropanecarboxylic acid [1-(2,3-dihydro-benzofuran-5-yl)-ethyl]- amide 1.40 (a) 342 3

2-(2-Fluoro-phenyl)- cyclopropanecarboxylic acid [1-(2,3-dihydro-benzofuran-5-yl)-ethyl]- amide 1.36 (a) 326 4

2-(3-Fluoro-phenyl)- cyclopropanecarboxylic acid [1-(2,3-dihydro-benzofuran-5-yl)-ethyl]- amide 1.37 (a) 326 5

2-(4-Fluoro-phenyl)- cyclopropanecarboxylic acid [1-(2,3-dihydro-benzofuran-5-yl)-ethyl]- amide 1.36 (a) 326 6

2-(2,5-Difluoro-phenyl)- cyclopropanecarboxylic acid [1-(2,3-dihydro-benzofuran-5-yl)-ethyl]- amide 1.38 (a) 344 7

2-Phenyl- cyclopropanecarboxylic acid [1-(2,3-dihydro-benzofuran-5-yl)-ethyl]- amide 1.33 (a) 308

Example 8 2-Phenyl-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide

[0155]

[0156] A mixture of (R)-2-amino-2-naphthalen-2-yl-ethanol (0.2 mmol),2-phenyl-cyclopropanecarboxylic acid (0.2 mmol), EDAC.HCl (0.4 mmol),DMAP (0.2 mmol), and triethylamine (0.6 mmol) in dichloromethane (2 mL)was stirred at room temperature for 12 h. The reaction mixture waspurified by flash chromatography eluting with 50% hexanes in ethylacetate to give the desired product (52 mg) as a solid.

[0157]¹H NMR (400 Hz, DMSO): δ 8.67-8.65 (m, 1 H), 7.88-7.84 (m, 4 H),7.49-7.46 (m, 3 H), 7.29-7.19 (m, 4 H), 5.05-4.92 (m, 2 H), 3.67-3.63(m, 2 H), 2.18-2.06 (m, 2 H), 1.30-1.17 (m, 2 H). MS (M+H)⁺ 332. HPLCrt: 1.39 min (method a)

Examples 9-15

[0158] Examples 9-15 were prepared from appropriate acids by the generalprocedure used to prepare Example 8. HPLC Mass Example rt (min), (M +H)⁺ No. Structure Chemical Name method m/z 9

2-(2-Chloro-phenyl)- cyclopropanecarboxylic acid(2-hydroxy-1-naphthalen-2- yl-ethyl)-amide 1.45 (a) 366 10

2-(3-Chloro-phenyl)- cyclopropanecarboxylic acid(2-hydroxy-1-naphthalen-2- yl-ethyl)-amide 1.53 (a) 366 11

2-(2-Fluoro-phenyl)- cyclopropanecarboxylic acid(2-hydroxy-1-naphthalen-2- yl-ethyl)-amide 1.39 (a) 350 12

2-(3-Fluoro-phenyl)- cyclopropanecarboxylic acid(2-hydroxy-1-naphthalen-2- yl-ethyl)-amide 1.43 (a) 350 13

2-(4-Fluoro-phenyl)- cyclopropanecarboxylic acid(2-hydroxy-1-naphthalen-2- yl-ethyl)-amide 1.40 (a) 350 14

2-(2,5-Difluoro-phenyl)- cyclopropanecarboxylic acid(2-hydroxy-1-naphthalen-2- yl-ethyl)-amide 1.44 (a) 368 15

2-(phenyl)- cyclopropanecarboxylic acid (2-hydroxy-1-naphthalen-2-yl-ethyl)-amide 1.39 (a) 332

Example 16 2-Phenyl-cyclopropanecarboxylic acid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide

[0159]

[0160] A mixture of(R)-2-amino-2-(4-fluoro-3-morpholin-4-yl-phenyl)-ethanol (0.1 mmol),2-phenyl-cyclopropanecarboxylic acid (0.1 mmol), EDAC.HCl (0.2 mmol),DMAP (0.1 mmol), triethylamine (0.4 mmol) in dichloromethane (2 mL) wasstirred at room temperature overnight. The reaction mixture was purifiedby flash chromatography with 3% methanol in ethyl acetate to give thedesired product (27 mg) as a solid.

[0161]¹H NMR (400 Hz, DMSO): δ 8.53-8.47 (m, 1 H), 7.28-6.96 (m, 47 H),4.86-4.84 (m, 2 H), 3.75-3.70 (m, 4 H), 53.52-3.50 (m, 2 H), 3.00-2.97(m, 4 H), 2.25-2.15 (m, 1 H), 2.04-2.01 (m, 1 H), 1.35-1.17 (m, 2 H). MS(M+H)⁺ 385. HPLC rt: 1.33 min (method a)

Examples 17-23

[0162] Examples 17-23 were prepared from appropriate acids by thegeneral procedure used to prepare Example 16. HPLC Mass Example rt(min), (M + H)⁺ No. Structure Name method m/z 17

2-(2-Chloro-phenyl)- cyclopropanecarboxylic acid [1-(4-fluoro-3-morpholin-4-yl-phenyl)- 2-hydroxy-ethyl]-amide 1.39, 1.44 (a) 419 18

2-(3-Chloro-phenyl)- cyclopropanecarboxylic acid [1-(4-fluoro-3-morpholin-4-yl-phenyl)- 2-hydroxy-ethyl]-amide 1.50, 1.55 (a) 419 19

2-(4-Chloro-phenyl)- cyclopropanecarboxylic acid [1-(4-fluoro-3-morpholin-4-yl-phenyl)- 2-hydroxy-ethyl]-amide 1.49, 1.54 (a) 419 20

2-(2-Fluoro-phenyl)- cyclopropanecarboxylic acid [1-(4-fluoro-3-morpholin-4-yl-phenyl)- 2-hydroxy-ethyl]-amide 1.42 (a) 403 21

2-(3-Fluoro-phenyl)- cyclopropanecarboxylic acid [1-(4-fluoro-3-morpholin-4-yl-phenyl)- 2-hydroxy-ethyl]-amide 1.39 (a) 403 22

2-(4-Fluoro-phenyl)- cyclopropanecarboxylic acid [1-(4-fluoro-3-morpholin-4-yl-phenyl)- 2-hydroxy-ethyl]-amide 1.38 (a) 403 23

2-(2,5-Difluoro-phenyl)- cyclopropanecarboxylic acid [1-(4-fluoro-3-morpholin-4-yl-phenyl)- 2-hydroxy-ethyl]-amide 1.38 (a) 421

Examples 24-31

[0163] Examples 24-31 were prepared by the general procedure: A mixtureof appropriate amine (0.1 mmol), appropriate cinnamic acid (0.1 mmol),EDC.HCl (0.2 mmol), DMAP (0.2 mmol), and triethylamine (0.4 mmol) indichloromethane (2 mL) was stirred at room temperature for 12 h. Thereaction mixture was purified by flash chromatography with 50% hexanesin ethyl acetate to give the titled compounds. HPLC Mass Example rt(min), (M + H)⁺ No. Structure Chemical name method m/z 24

2-(3-Fluoro-phenyl)- cyclopropanecarboxylic acid (1-naphthalen-2-yl-ethyl)-amide 1.54 (a) 334 25

2-(4-Fluoro-phenyl)- cyclopropanecarboxylic acid (1-naphthalen-2-yl-ethyl)-amide 1.62 (a) 334 26

2-(2,5-Difluoro-phenyl)- cyclopropanecarboxylic acid (1-naphthalen-2-yl-ethyl)-amide 1.56 (a) 352 27

2-Phenyl- cyclopropanecarboxylic acid (1-naphthalen-2-yl- ethyl)-amide1.53 (a) 316 28

2-(4-Fluoro-phenyl)- cyclopropanecarboxylic acid {1-[3-(3-dimethylamino- pyrrolidin-1-yl)-phenyl]- ethyl}-amide 1.15 (a) 396 29

2-(2,5-Difluoro-phenyl)- cyclopropanecarboxylic acid {1-[3-(3-dimethylamino- pyrrolidin-1-yl)-phenyl]- ethyl}-amide 1.10, 1.15 (a) 41330

2-(3-Fluoro-phenyl)- cyclopropanecarboxylic acid [1-(3-pyridin-3-yl-phenyl)-ethyl]-amide 1.08 (a) 361 31

2-(2,5-Difluoro-phenyl)- cyclopropanecarboxylic acid [1-(3-pyridin-3-yl-phenyl)-ethyl]-amide 1.09 (a) 379

Examples 32-36

[0164] Examples 32-36 were prepared by the general procedure: A mixtureof the appropriate cinnamic acid (0.083 mmol),(S)-1-(3-pyridin-3-yl-phenyl)-ethylamine (12.7 mg, 0.064 mmol), EDAC(18.4 mg, 0.096 mmol), HOBT (13 mg, 0.096 mmol), DMF (2 mL) anddiisopropylethylamine (33 μL, 0.192 mmol) was stirred at 23° C. for 18h. The residue was purified by preparative HPLC (Primeshere C18-HC21.2×100 mm; (5 mM NH₄OAc ) 0-100% gradient over 5 min; 20 mL/min flowrate) to afford the titled products. HPLC Mass Example rt (min), (M +H)⁺ No. Structure Chemical name method m/z 32

(S)-2-Phenyl- cyclopropanecarboxylic acid [1-(3-pyridin-3-yl-phenyl)-ethyl]-amide 1.75 (b) 343 33

(S)-2-(3-Fluoro-phenyl)- cyclopropanecarboxylic acid {1-[3-(6-fluoro-pyridin-3-yl)-phenyl]- ethyl}-amide 1.95 (b) 379 34

(S)-2-(3-Fluoro-phenyl)- cyclopropanecarboxylic acid {1-[3-(6-chloro-pyridin-3-yl)-phenyl]- ethyl}-amide 2.00 (b) 395 35

(S)-2-Phenyl- cyclopropanecarboxylic acid {1-[3-(2-fluoro-pyridin-3-yl)-phenyl]- ethyl}-amide 1.87 (c) 361 36

(S)-2-(2-Fluoro-phenyl)- cyclopropanecarboxylic acid {1-[3-(2-fluoro-pyridin-3-yl)-phenyl]- ethyl}-amide 1.91 (c) 379

What is claimed is:
 1. A compound of Formula I or a pharmaceuticallyacceptable salt thereof

wherein R is C₁₋₄ alkyl, CF₃ or hydroxymethyl; R¹ and R² are eachindependently hydrogen, C₁₋₄ alkyl, halogen or morpholin-4-yl; R⁴ isselected from the group consisting of optionally substitutedmorpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl, inwhich said substituent is independently selected from the groupconsisting of C₁₋₄alkyl, dimethylamino, hydroxymethyl, chloro andfluoro; R⁵ is hydrogen or fluoro; or R⁴ and R⁵ taken together are—CH═CH—CH═CH— or —CH₂CH₂O—; and R³, R⁶ and R⁷ are each independentlyselected from hydrogen or fluoro.
 2. The compound of claim 1 having theFormula Ic or a pharmaceutically acceptable salt thereof

wherein R is methyl or hydroxymethyl; R¹ and R² are each independentlyhydrogen, C₁₋₄ alkyl, halogen or morpholin-4-yl; R⁴ is selected from thegroup consisting of optionally substituted morpholin-4-yl, pyridinyl,pyrimidinyl, piperazinyl, and pyrazinyl, in which said substituent isindependently selected from the group consisting of C₁₋₄alkyl,dimethylamino, hydroxymethyl, chloro and fluoro; R⁵ is hydrogen orfluoro; or R⁴ and R⁵ taken together are —CH═CH—CH═CH— or —CH₂CH₂O—; andR³, R⁶ and R⁷ are each independently selected from hydrogen or fluoro.3. The compound of claim 1 selected from the group consisting of:2-(2-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide;2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide;2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide;2-(2-fluoro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide;2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide;2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide;2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide;2-(2-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide;2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide;2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide;2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide;2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid(1-naphthalen-2-yl-ethyl)-amide;2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid(1-naphthalen-2-yl-ethyl)-amide;2-(4-fluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyll}-amide;2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyl}-amide;2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid[1-(3-pyridin-3-yl-phenyl)-ethyl]-amide;2-(2,5-difluoro-phenyl)-cyclopropanecarboxylicacid[1-(3-pyridin-3-yl-phenyl)-ethyl]-amide;(S)-2-phenyl-cyclopropanecarboxylicacid[1-(3-pyridin-3-yl-phenyl)-ethyl]-amide;(S)-2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(6-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide;(S)-2-phenyl-cyclopropanecarboxylicacid{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide; and(S)-2-(2-fluoro-phenyl)-cyclopropanecarboxylicacid{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide; or apharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition for the treatment of disorders responsive to opening of KCNQpotassium channels comprising a therapeutically effective amount of thecompound of claim 1 in association with a pharmaceutically acceptablecarrier, adjuvant or diluent.
 5. A method for the treatment of disordersresponsive to opening of the KCNQ potassium channels in a mammal in needthereof, which comprises administering to said mammal a therapeuticallyeffective amount of the compound of claim
 1. 6. The method of claims 5wherein said disorders are acute and chronic pain, migraine, neuropathicpain, bipolar disorders, convulsions, mania, epilepsy, anxiety,depression and neurodegenerative disorders.
 7. The method of claim 6wherein said disorder is migraine.
 8. The method of claim 6 wherein saiddisorder is neuropathic pain.